The mechanism of formation of drug-protein complexes is being investigated by fast kinetic and spectroscopic methods in order to develop a clearer understanding of the molecular basis of drug specificity. Particular emphasis will be placed on the relationship between ligand structure, the elementary steps in the reaction scheme and macromolecular conformational changes accompanying complex formation. This should permit a more detailed interpretation of structure activity relationships for pharmacologic agents. Initial work has involved the investigation of three drug-enzyme systems which have purified to homogeneity: 1) carbonic anhydrase with aromatic sulfonamides and inhibitory anions, 2) acetyl cholinesterase with phenyl trimethylammonium and bis quaternary ammonium ligands. Complex formation kinetics will be followed by stopped-flow and temperature-jump methods. Inhibitor-induced or stabilized conformational changes on the respective complexes will be probed spectroscopically so that orientation of the bound ligand and conformational states of the complex and be correlated with the kinetics.